The incidence of kidney disease is ever increasing. None of the current therapies can improve regeneration of the injured kidneys. With the identification of stem cells in adult organs, and their potential role in tissue regeneration, cellular source of regenerating kidney is being reexamined. Stem cells reside in a protected microenvironment called "niche". Understanding of niche is critical in developing new therapies for prevention and treatment of kidney injury, and halting progression of kidney disease. Current understanding of the role-played by stem cells in renal repair and the kidney stem cell niche is in its infancy. This has markedly limited our ability to isolate, localize, and characterize kidney stem cells for therapeutic purposes. Our long-term goal is to develop new therapeutic strategies for prevention and treatment of renal diseases, based on improved understanding of stem cell biology. As a step to achieving our long-term goal, we put forward the following hypotheses to be tested in this research proposal: 1) A stem cell niche exists in the adult kidney, 2) Renal stem cells express the master stem cell gene Oct-4, 3) Renal stem cells have prolonged cell cycling time and preserved telomere length;4) Stem cells are mobilized in response to renal injury. We propose the following Specific Aims to test these hypotheses: Specific Aim 1: To generate a transgenic mouse line by "knock-in" of an inducible Cre-recombinase into the Oct-4 allele Specific Aim 2: To validate stemness of Oct-4 expressing cells present in adult kidney Specific Aim 3: To characterize the structural details of the renal stem cell niche On completion of the proposed research we will be able to determine the role played by stem cells in renal repair, characterize structural details of the stem cell niche in kidney, and develop a tool that will set the stage for in future studies defining the role of stem cells in regeneration, cancer formation, and aging, in kidney and other organs. This proposed research has high translational potential, and is expected to be of direct relevance in predicting, preventing, and treating kidney disease, a disease that has reached epidemic proportions. PUBLIC HEALTH RELEVANCE: Kidney disease has reached epidemic proportions with significant health and financial impact on the society. We are proposing to characterize kidney stem cells and determine their role in kidney regeneration that will form the basis for development of new therapeutic strategies for prevention, and treatment of kidney diseases.